Antiestrogens: Effects of tamoxifen, nafoxidine, and CI-628 on sexual behavior, cytoplasmic receptors, and nuclear binding of estrogen

Abstract

These experiments utilized the estrogen antagonists CI-628, nafoxidine, and tamoxifen as tools to investigate potential molecular mechanisms of estrogen activation of female rat sexual behavior. Adult female rats, ovariectomized 4–7 days previously and matched for body weight, were administered single sc injections of one of the three antiestrogens, and the ability of the antagonists to block estrogen-induced sexual behavior, to deplete and replenish hypothalamic estrogen receptors, and to inhibit the binding of estradiol by hypothalamic nuclei 2 hr, or 1, 2, 4, or 7 days later was assessed. All three compounds produced a dose- and time-dependent inhibition of estrogen-activated lordosis, with tamoxifen being the most potent inhibitor. The three antiestrogens also caused prolonged depletion of hypothalamic estrogen receptors, but there was no correlation between receptor levels and the degree of inhibition of lordosis behavior at any time point following antiestrogen treatment. Rats showed high levels of sexual receptivity when antiestrogens were injected 2, 4, or 7 days before estrogen; however, hypothalamic estrogen receptors were still markedly (up to 70%) reduced at some of these time points. In contrast, there was a large ( r = 0.67), significant correlation between the ability of all three agents to reduce [ 3H]estradiol binding by brain cell nuclei and their ability to reduce the display of estrogen-induced female sexual behavior. Antiestrogen injections which inhibited lordosis always decreased the level of specific estradiol binding by hypothalamic nuclei. These data indicate that delayed receptor replenishment does not adequately explain the antagonism of lordosis behavior by antiestrogens. The results presented here strongly point to the cell nucleus as the critical locus of receptor-mediated interactions which underlie estrogen and antiestrogen regulation of female sexual behavior.